Vascular Endothelial Growth Factor Signaling Research Articles

LncRNA H19 Promotes Angiogenesis in Mouse Pulmonary Artery Endothelial Cells by Regulating the HIF-1α/VEGF Signaling Pathway.

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of acute respiratory failure characterized by systemic hypoxemia and elevated pulmonary arterial pressure, which leads to pathological changes in pulmonary vascular remodeling and endothelial cell function. Long non-coding RNA (lncRNA) H19 has been shown to be involved in the regulation of arterial endothelial cell function, but its regulatory role in PPHN is not fully understood. In the present study, mouse pulmonary artery endothelial cells (MPAECs) were cultured in a hypoxic conditions. Subsequently, the regulatory function of lncRNA H19 on MPAECs was explored by constructing adenoviruses knocking down and overexpressing lncRNA H19. The results revealed that the hypoxic conditions could induce the proliferation and migration of MPAECs, as well as the high expression of lncRNA H19 in MPAECs. Knockdown of lncRNA H19 expression in MPAECs reversed hypoxic environment-induced functional changes in endothelial cells, whereas overexpression of lncRNA H19 further enhanced the proliferation and migration of MPAECs. In addition, lncRNA H19 upregulated the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway through sponge of miNA-20a-5p, which in turn promoted changes in endothelial cell function. LncRNA H19 may interfere with vascular remodeling in hypoxia-induced pulmonary hypertension by upregulating the expression of HIF-1α and VEGF in vascular endothelial cells.

Exploring the Promising Role of Guggulipid in Rheumatoid Arthritis Management: An In-depth Analysis.

Guggulipid, an oleo-gum resin extracted from the bark of Commiphora wightii of the Burseraceae family, holds a significant place in Ayurvedic medicine due to its historical use in treating various disorders, including inflammation, gout, rheumatism, obesity, and lipid metabolism imbalances. This comprehensive review aims to elucidate the molecular targets of guggulipids and explore their cellular responses. Furthermore, it summarizes the findings from in-vitro, in-vivo, and clinical investigations related to arthritis and various inflammatory conditions. A comprehensive survey encompassing in-vitro, in-vivo, and clinical studies has been conducted to explore the therapeutic capacity of guggulipid in the management of rheumatoid arthritis. Various molecular pathways, such as cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), PI3-kinase/AKT, JAK/STAT, nitric oxide synthase (iNOS), and NFκB signaling pathways, have been targeted to assess the antiarthritic and anti-inflammatory effects of this compound. The research findings reveal that guggulipid demonstrates notable antiarthritic and anti-inflammatory effects by targeting key molecular pathways involved in inflammatory responses. These pathways include COX-2, VEGF, PI3-kinase/AKT, JAK/STAT, iNOS, and NFκB signaling pathways. in-vitro, in-vivo, and clinical studies collectively support the therapeutic potential of guggulipid in managing rheumatoid arthritis and related inflammatory conditions. This review provides a deeper understanding of the therapeutic mechanisms and potential of guggulipid in the management of rheumatoid arthritis. The collective evidence strongly supports the promising role of guggulipid as a therapeutic agent, encouraging further research and development in guggulipid-based treatments for these conditions.

Loss of the Endothelial Glycocalyx Component EMCN Leads to Glomerular Impairment.

EMCN (endomucin), an endothelial-specific glycocalyx component, was found to be highly expressed by the endothelium of the renal glomerulus. We reported an anti-inflammatory role of EMCN and its involvement in the regulation of VEGF (vascular endothelial growth factor) activity through modulating VEGFR2 (VEGF receptor 2) endocytosis. The goal of this study is to investigate the phenotypic and functional effects of EMCN deficiency using the first global EMCN knockout mouse model. Global EMCN knockout mice were generated by crossing EMCN-floxed mice with ROSA26-Cre mice. Flow cytometry was used to analyze infiltrating myeloid cells in the kidneys. The ultrastructure of the glomerular filtration barrier was examined by transmission electron microscopy, whereas urinary albumin, creatinine, and total protein levels were analyzed from freshly collected urine samples. Expression and localization of EMCN, EGFP, CD45, CD31, CD34, podocin, and albumin were examined by immunohistochemistry. Mice were weighed regularly, and their systemic blood pressure was measured using a noninvasive tail-cuff system. Glomerular endothelial cells and podocytes were isolated by fluorescence-activated cell sorting for RNA sequencing. Transcriptional profiles were analyzed to identify differentially expressed genes in both endothelium and podocytes, followed by gene ontology analysis. Protein levels of EMCN, albumin, and podocin were quantified by Western blot. The EMCN-/- mice exhibited increased infiltration of CD45+ cells, with an increased proportion of Ly6GhighLy6Chigh myeloid cells and higher VCAM-1 (vascular cell adhesion molecule 1) expression. EMCN-/- mice displayed albuminuria with increased albumin in the Bowman's space compared with the EMCN+/+ littermates. Glomeruli in EMCN-/- mice revealed fused and effaced podocyte foot processes and disorganized endothelial fenestrations. We found no significant difference in blood pressure between EMCN knockout mice and their wild-type littermates. RNA sequencing of glomerular endothelial cells revealed downregulation of cell-cell adhesion and MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathways, along with glycocalyx and extracellular matrix remodeling. In podocytes, we observed reduced VEGF signaling and alterations in cytoskeletal organization. Notably, there was a significant decrease in both mRNA and protein levels of podocin, a key component of the slit diaphragm. Our study demonstrates a critical role of the endothelial marker EMCN in supporting normal glomerular filtration barrier structure and function by maintaining glomerular endothelial tight junction and homeostasis and podocyte function through endothelial-podocyte crosstalk.

The PLCG2 Inhibits Tumor Progression and Mediates Angiogenesis by VEGF Signaling Pathway in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) represents the most prevalent form of renal cell carcinoma. The management of early-stage ccRCC has a better prognosis, while patients with metastatic ccRCC have a lower five-year survival rate. Angiogenesis serves as the fundamental process underlying tumor metastasis. Therefore, it is crucial to discover new targets for angiogenesis to improve patient survival rates. The Cancer Genome Atlas database, International Cancer Genome Consortium database, Clinical Proteomic Tumor Analysis Consortium database, and a gene set of the vascular endothelial growth factor (VEGF) signaling pathway were utilized to identify differentially expressed genes. Western blot (WB), quantitative real-time polymerase chain reaction, and immunohistochemistry were employed to validate the downregulation of phospholipase C gamma 2 (PLCG2) in ccRCC tissues and cells. Cell Counting Kit-8 (CCK-8) assays, transwell assays, tube formation assays, and oil-red staining were performed to elucidate the biological functions of PLCG2 in tumor cells. Gene set enrichment analysis was applied to explore the downstream pathway. Subcutaneous tumor models and live small animal fluorescent imaging assay were utilized for in vivo investigation of the roles played by PLCG2. Our study has identified a novel biomarker, PLCG2, for ccRCC. PLCG2 is a central gene in regulating angiogenesis in ccRCC, as validated by bioinformatics analysis. The findings revealed a diminished expression of PLCG2 in both ccRCC tissues and cells. Further experiments in vivo and in vitro have demonstrated the significant roles of PLCG2 in tumor proliferation, invasion, migration, and lipid accumulation. Results of tube formation assays and WB support the role of PLCG2 in regulating VEGFA expression and angiogenesis. Our results show that PLCG2 functions as a potential biomarker and an independent prognostic indicator for ccRCC. PLCG2 may modulate angiogenesis by influencing the expression of VEGFA. Therefore, targeting PLCG2 could potentially lead to drug discovery and improved cancer treatment strategies.

Catalpol regulates apoptosis and proliferation of endothelial cell via activating HIF-1α/VEGF signaling pathway

Burn injuries, especially severe ones, causes microcirculation disorders in local wounds and distant tissues, leading to ischemia and hypoxia of body tissues and organs. The key to prevent and treat complications and improve prognosis after burns is to improve the state of ischemia and hypoxia of tissue and restore the blood supply of organs. Catalpol is an iridoid glycoside compound isolated from Rehmannia radix, which has been widely reported to have various of functions, including antioxidative stress, anti-inflammation, anti-apoptosis, and neuroprotection. However, the pharmacologic action and underlying mechanism of Catalpol in angiogenesis after burn injury remains unclear. The study investigated whether Catalpol regulates apoptosis and proliferation following vascular injury induced by burns using an in vitro model of oxygen-glucose deprivation (OGD) with a human umbilical vein endothelial (HUVE) cell line. The results showed that treatment with Catalpol reduces the level of apoptosis and promotes proliferation of endothelial cell. Mechanistically, Catalpol increases the expression of vascular endothelial growth factor (VEGF) by activating Hypoxia-inducible factor-1α (Hif-1α), resulting in increased expression of related downstream effector molecules. The current study suggested that Catalpol is a promising compound for endothelial protection in burns. It may be an efficient Hif-1α activator for endothelial cell deprived of oxygen and glucose.

AIP1 Regulates Ocular Angiogenesis Via NLRP12-ASC-Caspase-8 Inflammasome-Mediated Endothelial Pyroptosis.

Pathological ocular angiogenesis is a significant cause of irreversible vision loss and blindness worldwide. Currently, most studies have focused on the angiogenesis factors in ocular vascular diseases, and very few endogenous anti-angiogenic compounds have been found. Moreover, although inflammation is closely related to the predominant processes involved in angiogenesis, the mechanisms by which inflammation regulates pathological ocular angiogenesis remain obscure. In this study, a vascular endothelial cells (VECs)-specific anti-angiogenic factor is identified, apoptosis signal-regulating kinase 1(ASK1)-interacting protein-1 (AIP1) as a key pathogenic regulator in a typical ocular angiogenesis model, oxygen-induced retinopathy (OIR), using single-cell RNA sequencing. It is demonstrated that AIP1 inhibited pathological angiogenesis by preventing a particular inflammatory death pathway, namely pyroptosis, in retinal VECs. The assembly of a noncanonical inflammasome is further uncovered, the NLRP12-ASC-caspase-8 inflammasome, which is promoted by decreased AIP1 in OIR. This inflammasome elicited gasdermin D (GSDMD)-dependent endothelial pyroptosis, which in turn promoted the release of vascular endothelial growth factor (VEGF) and interleukin (IL)-1β. Suppression of NLRP12-CASP8-GSDMD axis and AIP1 upregulation reduced VEGF signaling, limiting new vessel formation. These findings reveal a previously uncharacterized inflammatory angiogenic process involving VECs pyroptosis-inducing retinal neovascularization, paving the way for promising therapeutic avenues targeting angiogenesis via AIP1 or pyroptosis.

Application of extracorporeal shockwave to regulate subchondral bone homeostasis through tumor necrosis factor-α/hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway in treatment of talus bone marrow edema.

To investigate the effect of extracorporeal shock wave on the treatment of talus bone marrow edema by regulating subchondral bone homeostasis through tumor necrosis factor-α (TNF-α)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway. A total of 81 patients with talus bone marrow edema admitted to our hospital from May 2019 to May 2021 were studied and divided into control group (n = 40) and extracorporeal shock group (n = 41) according to random number table method. The control group was given conventional treatment, and the extracorporeal shock group was combined with extracorporeal shock wave therapy on the basis of the control group. The expression of TNF-α, HIF-1α, and VEGF in the 2 groups were compared, pain degree, and the area of talus bone marrow edema was evaluated by magnetic resonance imaging. The visual analogue scale scores of 1 month, 2 months and 5 months after treatment were decreased in both groups, and the extracorporeal shock group was lower than the control group (P < .05). After 5 months of treatment, the expressions of TNF-α and HIF-1α were decreased in both groups, and the extracorporeal shock group was lower than the control group, VEGF was increased, and the extracorporeal shock group was higher than the control group (P < .05), and the western blot expression levels of TNF-α, HIF-1α and VEGF in the extracorporeal shock group were higher than the control group (P < .05). The dorsiflexion motion and plantar flexion motion of both groups were increased, and the extracorporeal shock group was higher than the control group (P < .05). Extracorporeal shock wave therapy can regulate subchondral bone homeostasis through TNF-α/HIF-1α/VEGF signaling pathway to treat talus bone marrow edema, reduce the pain degree of talus bone marrow edema, and improve ankle joint function.

Exploring the potential mechanisms of polysaccharides against gastric ulcer: Network pharmacology analysis and molecular docking validation

AbstractGastric ulcer is a common peptic ulcer that affects human health and life quality seriously. As anti‐gastric ulcer drugs usually cause side‐effects, polysaccharides may be the potential alternatives because of better effectiveness and less toxicity. Although the anti‐gastric ulcer activities of polysaccharides have been widely reported, the mechanisms have not yet been well‐disclosed. In this study, network pharmacology analysis was performed to explore the potential mechanisms of polysaccharides against gastric ulcer, and the results were validated by molecular docking. Results indicated that β‐glucan, arabinogalactan, xylan, and arabinan were the key structures, and ABL1, AKT1, androgen receptor, epidermal growth factor receptor, v‐Ha‐ras Harvey rat sarcoma viral oncogene homolog, HSP90AA1, mitogen‐activated protein kinase 8 (MAPK8), MAPK14, NOS2, PIK3R1, RAC1, ras homolog gene family member A, and proto‐oncogene tyrosine‐protein kinase Src were the core targets for polysaccharides in treating gastric ulcer. Polysaccharides have influences on 1958 GO items and 199 KEGG pathways, and their anti‐gastric ulcer activities are related to MAPK, Ras, PI3K‐Akt, vascular endothelial growth factor, prolactin, FoxO and Rap1 signaling pathways, etc. Molecular docking validation showed that the results of network pharmacology analysis were credible, and interactions between polysaccharide structures and core targets were observed. This study contributes to understanding the mechanisms of polysaccharides in treating gastric ulcer and provides references for future activity screening and mechanism research in anti‐gastric ulcer.

Reciprocal Dynamics of Metabolism and mRNA Translation in Tumor Angiogenesis.

Angiogenesis, the process of formation of new blood vessels from pre-existing vasculature, is essential for tumor growth and metastasis. Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF) signaling is a powerful tool to combat tumor growth; however, anti-tumor angiogenesis therapy has shown limited efficacy, with survival benefits ranging from only a few weeks to months. Compensation by upregulation of complementary growth factors and switches to different modes of vascularization have made these types of therapies less effective. Recent evidence suggests that targeting specific players in endothelial metabolism is a valuable therapeutic strategy against tumor angiogenesis. Although it is clear that metabolism can modulate the translational machinery, the reciprocal relationship between metabolism and mRNA translational control during tumor angiogenesis is not fully understood. In this review, we explore emerging examples of how endothelial cell metabolism affects mRNA translation during the formation of blood vessels. A deeper comprehension of these mechanisms could lead to the development of innovative therapeutic strategies for both physiological and pathological angiogenesis.

Laminin Beta 2 Is Localized at the Sites of Blood-Brain Barrier and Its Disruption Is Associated With Increased Vascular Permeability, Histochemical, and Transcriptomic Study.

Heterotrimeric extracellular matrix proteins laminins are mostly deposited at basal membranes and are important in repair and neoplasia. Here, we localize laminin beta 2 (LAMB2) at the sites of blood-brain barrier (BBB). Microvasculature (MV) of normal brain is endowed with complete LAMB2 coverage. In contrast, its cognate protein laminin beta 1 (LAMB1) is absent in MV of normal brain but emerges at the sprouting tip of a growing vessels. Similarly, vascular proliferation in high-grade gliomas (HGG) is accompanied by marked overexpression of LAMB1, whereas LAMB2 shows deficient deposition. We find that many brain pathologies with presence of post-gadolinium enhancement (PGE) on magnetic resonance imaging (MRI) show disruption of LAMB2 vascular ensheathment. Inhibition of vascular endothelial growth factor signaling in HGG blocks angiogenesis, suppresses PGE in HGG, prevents expression of LAMB1, and restores LAMB2 vascular coverage. Analysis of single-cell RNA sequencing (scRNA-seq) databases shows that in quiescent brain LAMB2 is predominantly expressed by BBB-associated pericytes (PCs) and endothelial cells (ECs), whereas neither cell types produce LAMB1. In contrast, in HGG, both LAMB1 and 2 are overexpressed by endothelial precursor cells, a phenotypically unique immature group, specific to proliferating hyperplastic MV.

Aberrant overexpression of myosin 1b in glioblastoma promotes angiogenesis via VEGF-myc-myosin 1b-Piezo1 axis

Glioblastoma (GBM) is the most aggressive intracranial malignancy with poor prognosis. Enhanced angiogenesis is an essential hallmark of GBM, which demonstrates extensive microvascular proliferation and abnormal vasculature. Here, we uncovered the key role of myosin 1b in angiogenesis and vascular abnormality in GBM. Myosin 1b is upregulated in GBM endothelial cells (ECs) compared to the paired non-malignant brain tissue. In our study, we found that myosin 1b promotes migration, proliferation and angiogenesis of human/mouse brain ECs. We also found that myosin 1b expression in ECs can be regulated by vascular endothelial growth factor (VEGF) signaling through myc. Moreover, myosin 1b promotes angiogenesis via Piezo1 by enhancing Ca2+ influx, in which process VEGF can be the trigger. In conclusion, our results identified myosin 1b as a key mediator in promoting angiogenesis via mechanosensitive ion channel component 1 (Piezo1) and suggested that VEGF/myc signaling pathway could be responsible for driving the changes of myosin 1b overexpression in GBM ECs.

Telencephalic stab wound injury induces regenerative angiogenesis and neurogenesis in zebrafish: unveiling the role of vascular endothelial growth factor signaling and microglia.

After brain damage, regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals, suggesting a close link between these processes. However, the mechanisms by which these processes interact are not well understood. In this work, we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury. To this end, we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms. First, using the Tg(fli1:EGFP × mpeg1.1:mCherry) zebrafish line, which enables visualization of blood vessels and microglia respectively, we analyzed regenerative angiogenesis from 1 to 21 days post-lesion. In parallel, we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry. We found that after brain damage, the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor (vegfaa and vegfbb) were increased. At the same time, neural stem cell proliferation was also increased, peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis, along with the recruitment of microglia. Then, through pharmacological manipulation by injecting an anti-angiogenic drug (Tivozanib) or Vegf at the lesion site, we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes, as well as microglial recruitment. Finally, we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis, as previously described, as well as injury-induced angiogenesis. In conclusion, we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process. In addition, we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes. This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.

Gene expression networks in endothelial cells from failing human hearts.

Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (n = 15) and healthy organ donors (n = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including CD34 and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway.NEW & NOTEWORTHY Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways.

Design, synthesis, and evaluation of antitumor activity in Pseudolaric acid B Azole derivatives: Novel and potent angiogenesis inhibitor via regulation of the PI3K/AKT and MAPK mediated HIF-1/VEGF signaling pathway

Tumor proliferation and metastasis are intricately linked to blood vessel formation, with vascular endothelial growth factor (VEGF) playing a pivotal role in orchestrating angiogenesis throughout tumor progression. Pseudolaric acid B (PAB) has emerged as a potent inhibitor of tumor cell proliferation, migration, and angiogenesis. In efforts to enhance its efficacy, 37 derivatives of PAB were synthesized and assessed for their capacity to suppress VEGF secretion in SiHa cells under hypoxic conditions. Notably, majority of these derivatives exhibited significant inhibition of VEGF protein secretion without inducing cytotoxicity. Among them, compound M2 displayed the most potent inhibitory activity, with an IC50 value of 0.68 μM, outperforming the lead compound PAB (IC50 = 5.44 μM). Compound M2 not only curbed the migration and angiogenesis of HUVECs under hypoxic conditions but also hindered the invasion of SiHa cells. Mechanistic investigations unveiled that compound M2 may impede the accumulation and nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) in SiHa cells, thereby downregulating VEGF expression. This inhibitory effect on HIF-1α was corroborated by experiments utilizing the protease inhibitor MG-132 and protein synthesis inhibitor CHX, indicating that compound M2 diminishes HIF-1α levels by reducing its synthesis. Furthermore, compound M2 was observed to modulate the PI3K/AKT/mTOR and MAPK signaling pathways in tumor cells, thereby regulating HIF-1α translation and synthesis. In vivo studies demonstrated that compound M2 exhibited low toxicity and effectively curbed tumor growth. Immunohistochemistry analyses validated that compound M2 effectively suppressed the expression of HIF-1α and VEGF in tumor tissues, underscoring its potential as a promising therapeutic agent for targeting tumor angiogenesis.

CBX7 promotes choroidal neovascularization by activating the HIF-1α/VEGF pathway in choroidal vascular endothelial cells

Vascular endothelial growth factor (VEGF) signaling is crucial for choroidal neovascularization (CNV), a major pathological feature of neovascular age-related macular degeneration (nAMD). Gene transcription of VEGF is mainly regulated by hypoxia-inducible factor 1-alpha (HIF-1α). The chromobox (CBX) family polycomb protein (Pc) subgroup includes CBX2, CBX4, CBX6, CBX7, and CBX8. CBX4 enhances hypoxia-induced VEGF expression and angiogenesis in hepatocellular carcinoma (HCC) cells by increasing HIF-1α′s transcriptional activity. The objective of the study was to examine the functions of members of the CBX family Pc subgroup in choroidal vascular endothelial cells (CVECs) during CNV. CBX4 and CBX7 expression was up-regulated in hypoxic human choroidal vascular endothelial cells (HCVECs). In HCVECs, CBX7 facilitated HIF-1α transcription and expression, while CBX4 did not. In HCVECs, CBX7 stimulated HIF-1α′s nuclear translocation and transcriptional activity, which in turn stimulated VEGF transcription and expression. The CBX7/HIF-1α/VEGF pathway promoted the migration, proliferation, and tube formation of HCVECs. The CBX7/HIF-1α/VEGF pathway was up-regulated in CVECs and in the mouse model with laser-induced CNV. Mouse CNV was lessened by the blockade of CBX7 through the down-regulation of HIF-1α/VEGF. In conclusion, CBX7 enhanced pro-angiogenic behaviors of hypoxic CVECs by up-regulating the HIF-1α/VEGF pathway, which contributing to the formation of mouse laser-induced CNV.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

A Nanocapsule System Combats Aging by Inhibiting Age-Related Angiogenesis Deficiency and Glucolipid Metabolism Disorders.

Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.

Integration of serum pharmacochemistry with network pharmacology to reveal the potential mechanism of Yangqing Chenfei formula for the treatment of silicosis.

To explore the mechanisms of Yangqing Chenfei formula (, YCF) in the treatment of silicosis through a comprehensive strategy consisting of serum pharmacochemistry, network pharmacology analysis, and in vitro validation. An ultrahigh-performance liquid chroma-tography-tandem mass spectrometry method was used to confirm the active components in YCF-medicated serum. Then, we obtained targets for active components and genes for silicosis from multiple databases. Furthermore, a protein-protein interaction network was constructed, and Kyoto Encyclopedia of Genes and Genomes pathway and biological process analyses were conducted to elucidate the mechanisms of YCF for the treatment of silicosis. Finally, we validated the important components and mechanisms in vitro. Altogether, 19 active components were identified from rat serum after YCF administration. We identified 724 targets for 19 components, which were mainly related to inflammation [phosphatidy linositol 3 kinase/protein kinase B, forkhead box O, hypoxia inducible factor, and T-cell receptor signaling pathway, nitric oxide biosynthetic process], fibrotic processes [vascular endothelial growth factor signaling pathway, extracellular signal regulated kinase (ERK) 1 and ERK2 cascade, smooth muscle cell proliferation], and apoptosis (negative regulation of apoptotic process). In addition, 218 genes for silicosis were identified and were mainly associated with the inflammatory response and immune process [cytokine?cytokine receptor interaction, tumor necrosis factor alpha (TNF-α), toll-like receptor, and nucleotide binding oligomerization domain-like receptor signaling pathway]. Taking an intersection of active component targets and silicosis genes, we obtained 61 common genes that were mainly related to the inflammatory response and apoptosis, such as the phosphatidylinositol-3-kinase/protein kinase B signaling pathway, mitogen activated protein kinases signaling pathway, TNF signaling pathway, toll-like receptor signaling pathway, biosynthesis of nitric oxide, and apoptotic process. In the herb-component-gene-pathway network, paeoniflorin, rutin and nobiletin targeted the most genes. In vitro, paeoniflorin, rutin and nobiletin decreased the mRNA levels of inflammatory factors [interleukin (IL)-6, TNF-α, and IL-1β], suppressed p-AKT and cleaved caspase-3, and increased B cell lymphoma (Bcl)-2 protein expression in silica-induced macrophages in a concentration-dependent manner. YCF could significantly relieve the inflammatory response of silicosis via suppression of the AKT/Bcl-2/Caspase-3 pathway.

PDCL3 as a prognostic factor and associated with the VEGF signaling pathway in glioma.

New targeted drugs about angiogenesis could develop the treatment of glioma. We aimed to explore the role of phosducin like 3 (PDCL3) in angiogenesis of glioma. RNA sequencing data and matched clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. To screen for the reliable genes with the filtering analyses, survival, multivariate Cox, receiver operating characteristic (ROC) curve filtration, and clinical correlation analyses were performed. The PDCL3 gene was validated by immunohistochemistry as a reliable gene for further analysis. Then we used the combined data of TCGA and Genotype-Tissue Expression from UCSC to detect the differential gene expression of PDCL3. Related signal pathways in glioma were explored by the gene set enrichment analysis and co-expression analysis. Lastly, we performed in vitro experiments to verify the gene functions and related mechanisms. The three filtering analyses and immunostaining indicated that the expression of PDCL3 in glioma tissues was higher than the normal tissues. Gene function analysis showed that PDCL3 activated the vascular endothelial growth factor (VEGF) signal pathway, and its mechanism was related to pathways in cancer, like NOD like receptor signaling pathway, the RIG-I like receptor signaling pathway and the P53 signaling pathway by MAPK/AKT in gliomas. This suggested that the proliferation, migration and invasion of glioma cells might be inhibited by the downregulation of PDCL3 in vitro, which may be related to the activation of VEGF signaling pathway. We demonstrated that PDCL3 could function as an independent adverse prognostic marker in glioma. Its pro-oncogenic mechanism may be related to the VEGF signaling pathway.

Expression and Transcriptional Targets of TGFβ-RII in Paracentrotus lividus Larval Skeletogenesis.

Organisms from the five kingdoms of life use minerals to harden their tissues and make teeth, shells and skeletons, in the process of biomineralization. The sea urchin larval skeleton is an excellent system to study the biological regulation of biomineralization and its evolution. The gene regulatory network (GRN) that controls sea urchin skeletogenesis is known in great details and shows similarity to the GRN that controls vertebrates' vascularization while it is quite distinct from the GRN that drives vertebrates' bone formation. Yet, transforming growth factor beta (TGF-β) signaling regulates both sea urchin and vertebrates' skeletogenesis. Here, we study the upstream regulation and identify transcriptional targets of TGF-β in the Mediterranean Sea urchin species, Paracentrotus lividus. TGF-βRII is transiently active in the skeletogenic cells downstream of vascular endothelial growth factor (VEGF) signaling, in P. lividus. Continuous perturbation of TGF-βRII activity significantly impairs skeletal elongation and the expression of key skeletogenic genes. Perturbation of TGF-βRII after skeletal initiation leads to a delay in skeletal elongation and minor changes in gene expression. TGF-β targets are distinct from its transcriptional targets during vertebrates' bone formation, suggesting that the role of TGF-β in biomineralization in these two phyla results from convergent evolution.